1. Field of the Invention
The present invention is directed to 1,11-diesters of prostaglandin F2.alpha. which have a polar ester group at the C-1 position. The compounds are active as agents for decreasing intraocular pressure in the mammalian eye.
2. Background Art
Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.
Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
The underlying causes of primary glaucoma are not yet known. The increased intraocular tension is due to the obstruction of aqueous humor outflow. In chronic open-angle glaucoma, the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded. In acute or chronic angle-closure glaucoma, the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupillary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm. Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe and may plug the drainage channel with exudates. Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
Considering all types together, glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision. In cases where surgery is not indicated, topical B-adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
Prostaglandins can be described as derivatives of prostanoic acid, the structure and numbering of which is shown in Formula 1. The term prostaglandin F2.alpha. describes a prostaglandin compound which has the structure shown in Formula 2. ##STR2##
Prostagladins were earlier regarded as potent ocular hypertensives; however, evidence accumulated in the last two decades shows that some prostaglandins are highly effective ocular hypotensive agents and are ideally suited for the long-term medical management of glaucoma. (See, for example, M. S. Starr, Exp. Eye Res. 11, 170-177, (1971); Bito, L. Z. Biological Protection with Prostaglandisn Cohen, M. M., ed., Boca Raton, Fla. CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the Medical Treatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune & Stratton, 1984, pp. 477-505). Such prostagladins include PGF.sub.2.alpha., PGF.sub.1.alpha., PGE.sub.2, and certain lipid-soluble esters, such as C.sub.1 to C.sub.5 alkyl esters, e.g. 1-isopropyl ester, of such compounds.
In the U.S. Pat. No. 4,599,353 certain prostaglandins, in particular PGE.sub.2 and PGF.sub.2.alpha. and the C.sub.1 to C.sub.5 alkyl esters of the latter compound, were reported to possess ocular hypotensive activity and were recommended for use in glaucoma management.
Although the precise mechanism is not yet known, recent experimental results indicate that the prostaglandin-induced reduction in intraocular pressure results from increased uveoscleral outflow [Nilsson et al., Invest, Ophthalmol. Vis. Sci. 28 (suppl), 284 (1987)].
The isopropyl ester of PGF.sub.2.alpha. has been shown to have significantly greater hypotensive potency than the parent compounds, which was attributed to its more effective penetration through the cornea. In 1987 this compound was described as "the most potent ocular hyptensive agent ever reported." [See, for example, Bito, L. Z., Arch. Ophthalmol, 105, 1036 (1987), and Siebold et al., Prodrug 5, 3 (1989)].
Whereas prostagladins appear to be devoid of significant intraocular side effects, ocular surface (conjunctival) hyperemia and foreign-body sensation have been consistently associated with the topical ocular use of such compounds, in particular PGF.sub.2.alpha. and its prodrugs, e.g. its 1-isopropyl ester, in humans. The clinical potential of postaglandins in the management of conditions associated with increased ocular pressure, e.g. glaucoma, is greatly limited by these side effects.
Certain phenyl and phenoxy mono, tri and tetra nor prostaglandins and their 1-esters are disclosed in European Patent Application 0,364,417 as useful in the treatment of glaucoma or ocular hypertension.
In a series of co-pending United States patent applications assigned to Allergan, Inc. prostaglandin esters with increased ocular hypotensive activity accompanied with no or substantially reduced side-effects are disclosed. The co-pending U.S. Ser. No. 596,430 relates to certain 11-acyl-prostaglandins, such as 11-pivaloyl, 11-acetyl, 11-isobutyryl, 11-valeryl, and 11-isovaleryl PGF.sub.2.alpha.. Intraocular pressure reducing 15-acyl prostaglandins are disclosed in the co-pending application U.S. Ser. No. 967,586. Similarly, 11,15- 9,15 - and 9,11-diesters of prostaglandins, for example 11,15-dipivaloyl PGF.sub.2.alpha. are known to have ocular hypotensive activity. See U.S. Pat. No. 4,494,274; co-pending application 584,370, and U.S. Pat. No. 5,034,413.
U.S. Pat. No. 5,139,491 assigned to Allergan Inc. discloses 2-decarboxyl-2-alkoxyalkyl prostaglandins, including for example 2-decarboxyl-2-methoxymethyl prostaglandin F.sub.2.alpha. as ocular hypotensive agents. Co-pending application Ser. No. 07/538,204 filed on Jun. 14, 1990 (now allowed) discloses PGF 1-alcohols.
Generally speaking, whereas derivatives of prostaglandin F.sub.2.alpha. where the 11-OH group is acylated and the 1-COOH group is alkylated have intraocular hypotensive activity, these compounds have low solubility in water. It is therefore desirable to provide such further prostaglandin F.sub.2.alpha. derivatives which have reasonable aqueous solubility coupled with intraocular hypotensive activity.